Sunlight-induced skin cancer is the most prevalent cancer in the United States, and UVB is primarily responsible for these cancers. Our studies indicated that oral administration of caffeine or voluntary running wheel exercise (a) decreases tissue fat, (b) inhibits UVB-induced skin carcinogenesis, and (c) enhances apoptosis in UVB-treated epidermis and in skin tumors in SKH-1 mice. We also found that partial lipectomy enhances UVB-induced apoptosis in the epidermis. Our preliminary studies suggest that oral administration of caffeine when combined with voluntary exercise may have a synergistic effect in decreasing tissue fat and stimulating UVB-induced apoptosis. We plan to pursue the following specific aims: 1. Determine the possible molecular mechanisms of voluntary running wheel exercise in combination with orally administered caffeine for 2 weeks on UVB-induced modulation of the p53-independent, ATR/Chk1/cyclin B1-mediated pathway that leads to lethal mitosis (apoptosis) in the epidermis of SKH-1 mice. 2. Determine the effects of removal of the parametrial fat pad (partial lipectomy) on UVB-induced apoptosis and modulation of the p53-independent, ATR/Chk1/cyclin B1-mediated pathway that leads to lethal mitosis (apoptosis) in the epidermis of SKH-1 mice. Effects of exercise in combination with caffeine on UVB-induced apoptosis in the epidermis of partially lipectomized SKH-1 mice will also be studied. 3. Determine the possible synergistic inhibitory effect of exercise in combination with caffeine on UVB-induced skin carcinogenesis in SKH-1 mice. Determine the possible molecular mechanisms of these treatments as well as partial lipectomy on the ATR/Chk1/cyclin B1-mediated pathway that leads to lethal mitosis (apoptosis) in tumors and in areas of the epidermis away from tumors. Possible cytokines that are associated with enhanced skin carcinogenesis will be studied. PUBLIC HEALTH RELEVANCE: RELEVANCE TO PUBLIC HEALTH Since physical exercise and/or caffeine intake are conducted by very large segments of the population, research on possible synergy and mechanisms of the potential anticancer effects of exercise, caffeine ingestion and/or fat removal may have broad human significance for cancer prevention.